Calcium gluconate solutions in flexible containers

ABSTRACT

A terminally sterilized aqueous calcium gluconate solution comprising 1 to 15 wt. % calcium gluconate and from 1 to 19 wt. parts of calcium saccharate per 100 wt. parts of calcium gluconate packaged in a flexible plastic container with the remainder water.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. Ser. No. 15/868,705 filedJan. 11, 2018, allowed, which is a continuation of U.S. Ser. No.15/659,184 filed Jul. 25, 2017, abandoned, the entire contents of whichare incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to aqueous calcium gluconate solutions in flexibleplastic bags. The solution in the bag is terminally sterilized.

BACKGROUND OF THE INVENTION

Calcium gluconate is used for treating individuals having low levels ofcalcium ions in their blood system. Often the calcium gluconate isadministered orally. However, in more serious calcium deficiencyconditions, it is necessary to rapidly increase the amount of calciumions in the person's blood system which requires administration ofcalcium via intravenous means. When the individual with the hypocalcemiais a child, in a pediatric intensive care unit, it is almost bynecessity that the calcium gluconate is administered intravenously. Insevere cases, there could be life threatening complications includingcardiac arrhythmias.

Calcium gluconate is an old drug dating back to at least the 1930s, andis available as aqueous solutions of calcium gluconate in 10 mL glassvials and 100 mL rigid plastic bottles. Calcium gluconate is sold as asupersaturated solution which must be administered at a slow rate. Theglass vials have a number of disadvantages. First, is the possibility ofbreakage with the scattering of glass particles. Second, for glass vialsand plastic bottles it is necessary to often dilute the calciumgluconate solution in an IV bag so as to allow intravenous (IV)administration at the appropriate rate. Finally, both the glass andrigid plastic containers take up more storage space than the flexibleplastic bag products used for IV administration of drugs and othersolutions.

Mixtures of calcium gluconate with calcium saccharate are described inU.S. Pat. No. 1,965,535. This patent teaches preparing calcium gluconatesolutions containing calcium saccharate as a stabilizer which can bestored in glass containers after suitable sterilization or the use of apreservative agent. The patent cautions that the solution must beprotected from “infection” since fermentation readily occurs in thepresence of microorganisms.

Hospitals avoid the use of glass and rigid plastic vials and bottles inpatient rooms and either will directly transfer the calcium gluconatefrom the container into plastic bags, which are then used for IVadministration or have such bags prepared in advance by adding thecalcium gluconate solution to an IV solution. Such pre-prepared bags maybe done at the hospital or by a compounder. However the bags so preparedhave a limited shelf life at room temperature, typically on the order ofabout 45 to 70 days. Unused product cannot be used after the expirationdate and must be properly disposed of. As a result, hospitals cannotmaintain a significant inventory of the calcium gluconate in the plasticIV bags but must often replenish their supply.

In contrast, the calcium gluconate solutions sold in glass and rigidplastic vials are reported to have shelf lives of about three years.Thus, there exists a need for a calcium gluconate aqueous solutionproduct in plastic bags which has a long shelf life.

SUMMARY OF THE INVENTION

This invention relates to aqueous calcium gluconate solutions which havelong-term storage stability when stored in a flexible plastic container.The calcium gluconate solution in the flexible plastic container issubjected to terminal sterilization via moist-heat autoclaving so thatthe product is in a sterile condition. The product in the bag can beadministered to the patient using conventional IV technology. Thecalcium gluconate solution will conventionally contain, in addition tothe calcium gluconate, calcium saccharate as a stabilizer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Calcium gluconate aqueous solutions are most commonly available as supersaturated solutions containing about 15 mg/mL-25 mg/mL calciumgluconate, 0.6 mg/mL-1.5 mg/mL calcium saccharate, sufficient sodiumchloride to provide an isotonic solution. A more preferred solutioncomprises 19.6 mg/ml of calcium gluconate monohydrate, about 0.9 mg/mlof calcium D-saccharate, about 6.75 mg/ml sodium chloride to adjusttonicity and hydrochloric acid or sodium hydroxide to adjust the pH asneeded. The pH will often be adjusted to about 7-8, the psychological pHbut a higher or lower pH is possible. Normally the pH will be between 5and 8.5, more preferably between 6.0 and 8.2, and most preferablybetween 7 and 8. The sodium chloride may be replaced in whole or in partby a sufficient quantity of calcium chloride or potassium chloride or amixture of both in an amount sufficient to provide an isotonic solution.A solution is considered to be isotonic if it has an osmolality ofbetween about 260 and 320 mosm/kg. The use of sugars such as dextroseshould be avoided as they may impact the stability of the solution toterminal sterilization and adversely impact the storage life of thesolution. The calcium saccharate is added to stabilize thesupersaturated calcium gluconate solution. The calcium D-saccharate hasbeen found to be particularly suitable for this purpose. Other calciumsaccharates may be used provided the resulting supersaturated solutionis stable. The suitability of other calcium saccharates can bedetermined using the procedure described in U.S. Pat. No. 1,965,535which incorporated herein by reference. Solutions having lower calciumgluconate concentrations are also included.

The calcium gluconate concentration in the formulation is not limited.Concentrations of from 1 to about 15 wt. % are preferred, still morepreferred are concentrations of about 6 to 12 wt. %, with the mostpreferred being about 10 wt. %. The amount of calcium gluconate in thesolution is limited by the calcium gluconate's solubility in the aqueousmedium. Solutions of from 1 to 10% calcium gluconate require about 1 to19 parts of calcium saccharate per 100 parts of calcium gluconate. For a10% calcium gluconate solution, the amount of calcium saccharate is fromabout 2 parts to 5 parts per 100 hundred parts of calcium gluconate. Allparts are by weight. The maximum calcium saccharate solubility incalcium gluconate solution is about 19 parts per 100 parts calciumgluconate.

The amount of the tonicity adjusting agent added is usually an amountsufficient to make the solution isotonic. The tonicity adjusting agentmay be omitted if an isotonic solution is not required. While sodiumchloride is a common tonicity adjusting agent, any of the conventionaltonicity adjusting agents may be used provided the agent does notadversely impact the stability of the solution.

The preferred composition comprises 19.6 mg/ml of calcium gluconatemonohydrate, about 0.9 mg/ml of calcium D-saccharate, and about 6.75mg/ml sodium chloride to adjust tonicity and hydrochloric acid or sodiumhydroxide to adjust the pH as needed. Other physiologically acceptedacids and bases may be used to adjust the pH of the solution. Normallythe pH is adjusted from 5.5 to about 8.5, preferably from about 6 to8.2.

Calcium gluconate solutions are compatible with the followingintravenous solutions and drugs: sodium chloride for injection 0.9%,lactated Ringer's injection, dextrose 5%-20%, dextrose-lactated Ringer'sinjection, dextrose-saline combinations, amikacin sulfate,aminophylline, ascorbic acid injection, bretylium tosylate, cephapirinsodium, chloramphenicol sodium succinate, corticotropin, dimenhydrinate,erythromycin gluceptate, heparin sodium, hydrocortisone sodiumsuccinate, lidocaine HCl, methicillin sodium, norepinephrine bitartrate,penicillin G potassium/sodium, phenobarbital sodium, potassium chloride,tobramycin sulfate, vancomycin HCl, verapamil and vitamin B-complex withC.

The calcium gluconate solutions of the invention should be free ofagents which will cause the calcium gluconate to precipitate fromsolution. Materials which may impact the calcium gluconate solutionsinclude phosphate salts, oxytetracycline HCl, prochlorperazineedisylate, and tetracycline HCl. Compatibility is dependent upon factorssuch as pH, concentration, temperature and diluents used. If thesematerials are to be included the solution, the stability of the calciumgluconate solution should be investigated.

Calcium gluconate is reportedly incompatible with the followingsolutions or drugs: intravenous fat emulsion, amphotericin B,cefamandole naftate, cephalothin sodium, dobutamine HCl,methylprednisolone sodium succinate, and metoclopramide HCl.

The flexible plastic container must be one which is compatible withcalcium gluconate. It must also be able to undergo heat sterilization inmoist steam without contaminating the calcium gluconate solution.Suitable flexible plastic containers are those made of copolymerizedethylene and vinyl acetate. Preferably the bag is laminated with theinner most layer comprising copolymerized ethylene and vinyl acetate.More preferably the bag comprises from 3 to 7 layers. These materialsare commercially available under the tradename Nexcel® by Sealed Air.The volume of the bag is dependent on the volume of premixed formula.The volume of premixed formula can be from 10 ml to 1000 ml, preferable50 ml and 100 ml based on current calcium gluconate dosing. Larger orsmaller volumes can be used depending on dosing requirements. CR3elastomer copolyester ether bags may also be used for formulations to besterilized in moist steam provided but are not preferred.

In an embodiment of the present invention, provided are a flexibleplastic container with modified ports and closure system suitable forstoring Calcium gluconate formulations of the present invention which issubjected to typically product sterilization by steam sterilization(e.g., autoclaving, 121° C. for about 20 minutes) without altering thethermal properties of the film layers, ports and closure system as wellas maintaining the integrity container. The primary polymeric materialswhich may be used include: polysulfone, polycarbonate, polypropylene,polyethylene (LDPE or HDPE), ethylene/propylene copolymers, polyolefins,acrylic-imide copolymers, polyester (e.g. PET, PEN and the like),Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC,ethylvinylacetate, AN-copolymer etc. In addition to plastic bags, CZresin containers, polypropylene and similar resins can be used as rigidcontainers and syringes.

The ports and the closure system preferably uses commerciality availablepolymers, elastomers etc. In an exemplary embodiment of the presentinvention, the administrative and additive ports can be made offexternal coextruded layer consists of synthetic thermoplastic rubber(Raumedic SRT320) ranging from about 20 to 30% based on an elastomermodified polypropylene. While the internal coextruded layer (PE770) ofnot more that 50% in composition consists of ethylene vinyl acetatewithout any further additives (EVA). The tubing ports can be made oftwo-layer materials, which can withstand both terminal sterilization andco-solvent matrix. Furthermore, the twist-off compositions can be madeof polyproplene Granuflex® 4489 between 70-80% and Granuflex®437115-20%. Alternatively the port tube may be a bilayer tube comprising anouter layer of polypropylene and an inner layer of EVA and the twist offmade of LDPE and PP. However, other polymers stable, low leachables, andwithout physical deformation during heat sterilization may also be usedfor the ports and closure assemblies.

Commercially available flexible plastic containers (bags) such as Excel®(Braun Company) comprising a three-layered ethylene-polypropylene baghaving polyester elastomer outer layer, Visiv® (Hospira), Nexcel®(Sealed Air), Intervia® (Baxter) preferably with a non-DEHP fluid path,Technoflex polyolefin bags, etc., for pharmaceutical formulation ormedical liquids are assembled of different plastic materials ofdifferent properties, thermal resistance and functionalities. They aretypically designed and tested mostly for aqueous formulationsadmixtures, premixed or ready-to-use pharmaceutical products. Still thecombination of the co-solvents and drug composition subjected to furtherheat sterilization can adversely effect, plastic materials, sealingintegrity and the solutions contained therein unless they are maintainedat certain conditions. Thus, the plastic container should be checkedafter sterilization for integrity before using it for the formulation.In addition, the formulation after sterilization should be analyzed forthe presence of substances leached from the container as a result of thesterilization cycle.

In another alternative embodiment, provided are a flexible plasticcontainer with modified ports and closure system suitable for storingcalcium gluconate formulations of the present invention which issubjected to typically product sterilization by steam sterilization(e.g., autoclaving, 121° C. for about 15 to 20 minutes) without alteringthe thermal properties of the film layers, ports and closure system aswell as maintaining the integrity container. The primary polymericmaterials which may be used include: polysulfone, polycarbonate,polypropylene, polyethylene (LDPE or HDPE), ethylene/propylenecopolymers, polyolefins, acrylic-imide copolymers, polyester (e.g. PET,PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene,PVDC, ethylvinylacetate, AN-copolymer etc.

Sterilization is accomplished by heat sterilization. Heat sterilizationis normally performed using steam, preferably wet steam to allow for theuse of pressure as a means of temperature control. The time period forthe sterilization must be long enough to meet the sterility requirementsrequired of an injectable product. When steam is used the period may befrom about 5 to 30 minutes at temperatures of about 110° C. to 130° C.,or from about 10 to 30 minutes at temperatures of about 110° C. to 130°C., preferably at 120° C. to 125° C. for 15 to 30 minutes. In anotherembodiment, the sterilization can be at 120° C. for 5 to 20 minutes.

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples, which areprovided herein for purposes of illustration only, and are not intendedto be limiting unless otherwise specified.

In the examples which follow, the compositions were made as follows:

The formulation was packaged in 100 mL bags. One portion was used tofill the 100 mL Nexcel M312A Bag 1P with 50 mL of the calcium gluconatesolution and the second was used to fill the same Nexcel bags with 100mL of the solution. The bags were then terminally sterilized in a steamautoclave at 121° C. for 20 minutes. After sterilization the bags weresubjected accelerated stability testing at 40° C.±2° C./15% RH±5% RH. Inexample 1 the results for the bags with the 50 mL solution are reportedand in Example 2 the results for the 100 mL solution are reported.

EXAMPLE 1 50 mL Bag Containing 1 Gram Calcium Gluconate

Test (U.M.) Shelf life 0 1 2 3 6 Clear, Colorless solution (—) CompliesComplies Complies Complies Complies Complies Free from visible particles(—) Complies Complies Complies Complies Complies Complies pH (pH Units)6.0-8.2 6.6 6.3 6.2 6.3 6.3 Osmolality (mOSmo/Kg) 270-320 298 304 297306 311 Assay Calcium (% Labelled  95.0-105.0 101.1 101.2 101.1 101.6101.3 Claim) Assay Chloride (mmol/L) 109.7-121.3 116.1 116.0 116.4 117.2116.9 Extractable Volume (ml) >=50 53.7 53.7 53.7 53.7 53.7 Weight Loss(%) <=2.0 0.0 0.0 0.0 0.0 0.0 Particles >= 10 micron (N. <=6000 0 100 5050 0 Part/Bag) Particles >= 25 micron (N. <=600 0 0 0 0 0 Part/Bag)Bacterial Endotoxins (EU/mg) <0.17 <0.08475 — — — <0.08475 Sterility(Parametric Release Comply Comply — — — — per SOP GEN094) (—) Sterility(Container Integrity) (—) Comply — — — — Comply

EXAMPLE 2 100 mL Bag Containing 2 Grams of Calcium Gluconate

Test (U.M.) Shel life 0 1 2 3 6 Clear, Colorless solution (—) CompliesComplies Complies Complies Complies Complies Free from visible particles(—) Complies Complies Complies Complies Complies Complies pH (pH Units)6.0-8.2 6.7 6.3 6.3 6.3 6.4 Osmolality (mOSmo/Kg) 270-320 301 297 301302 307 Assay Calcium (% Labelled  95.0-105.0 99.8 99.7 99.6 99.9 99.4Claim) Assay Chloride (mmol/L) 109.7-121.3 114.5 114.9 114.6 115.2 114.9Extractable Volume (ml) >=100 104.0 104.0 104.0 104.0 104.0 Weight Loss(%) <=2.0 0.0 0.0 0.0 0.0 0.0 Particles >= 10 micron (N. <=6000 200 200100 100 0 Part/Bag) Particles >= 25 micron (N. <=600 0 0 0 0 0 Part/Bag)Bacterial Endotoxins (EU/mg) <0.17 <0.08475 — — — <0.08475 Sterility(Parametric Release Comply Comply — — — — per SOP GEN094) (—) Sterility(Container Integrity) (—) Comply — — — — Comply

As can be seen from the results, the calcium gluconate solution wasvirtually unchanged after six months of accelerated stability testing inboth examples. This test is equivalent of 24 months at 25° C.+/−2° C.and 40%±5% relative humidity. These results are surprising in view ofthe prior art disclosures of only a short shelf life for the prior artcalcium gluconate bag formulations.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

The invention claimed is:
 1. A terminally sterilized aqueous calciumgluconate solution comprising 1 to 15 wt. % calcium gluconate and from 1to 19 wt. parts of calcium saccharate per 100 wt. parts of calciumgluconate packaged in a flexible plastic container with the remainderwater, wherein the solution has a pH of from 6.0 to 8.2.
 2. Theterminally sterilized aqueous calcium gluconate solution of claim 1wherein the flexible container is a bag.
 3. The terminally sterilizedaqueous calcium gluconate solution of claim 2 further comprising atonicity agent.
 4. The terminally sterilized aqueous calcium gluconatesolution of claim 1 wherein the solution has a pH of from 6.0 to 6.7. 5.The terminally sterilized aqueous calcium gluconate solution of claim 1wherein the solution has a pH of from 6.2 to 6.7.